Bronowicka-Adamska Patrycja, Szlęzak Dominika, Bentke-Imiolek Anna, Kaszuba Kinga, Majewska-Szczepanik Monika
Jagiellonian University Medical College, Faculty of Medicine, Chair of Medical Biochemistry, 7c Kopernika st., 31-034, Cracow, Poland.
Jagiellonian University Medical College, Faculty of Medicine, Chair of Medical Biochemistry, 7c Kopernika st., 31-034, Cracow, Poland.
Biochimie. 2025 May;232:66-73. doi: 10.1016/j.biochi.2025.01.008. Epub 2025 Jan 25.
Obesity treatment requires an individualized approach, emphasizing the need to identify metabolic pathways of diagnostic relevance. Toll-like receptors (TLRs), particularly TLR2 and TLR4, play a crucial role in metabolic disorders, as receptor deficiencies improves insulin sensitivity and reduces obesity-related inflammation. Additionally, hydrogen sulfide (HS) influences lipolysis, adipogenesis, and adipose tissue browning through persulfidation. This study investigates the impact of a high-fat diet (HFD) on low molecular weight sulfur compounds in the visceral adipose tissue (VAT) of C57BL/6 and TLR2-deficient mice. It focuses on key enzymes involved in HS metabolism: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CGL), 3-mercaptopyruvate sulfurtransferase (MPST), and thiosulfate sulfurtransferase (TST). In C57BL/6 mice on HFD, MPST activity decreased, while CBS level increased, potentially compensating for HS production. In contrast, TLR2-deficient mice on HFD exhibited higher MPST activity but reduced level of CBS and CGL activity, suggesting that TLR2 deficiency mitigates HFD-induced changes in sulfur metabolism. TST activity was lower in TLR2-deficient mice, indicating an independent regulatory role of TLR2 in TST activity. Elevated oxidative stress, reflected by increased glutathione levels, was observed in wild-type mice. Interestingly, cysteine and cystine were detectable only in the VAT of the C57BL/6 ND group and were absent in all other groups. The capacity for hydrogen sulfide production in tissues from TLR2-/-B6 HFD group was significantly lower than in the C57BL/6 HFD group. In conclusion, TLR2 modulates sulfur metabolism, oxidative stress, and inflammation in obesity. TLR2 deficiency disrupts HS production and redox balance, potentially contributing to metabolic dysfunction, highlighting TLR2 as a potential therapeutic target for obesity-related metabolic disorders.
肥胖治疗需要个体化方法，强调识别具有诊断相关性的代谢途径的必要性。Toll样受体（TLR），尤其是TLR2和TLR4，在代谢紊乱中起关键作用，因为受体缺陷可提高胰岛素敏感性并减少肥胖相关炎症。此外，硫化氢（HS）通过过硫化作用影响脂肪分解、脂肪生成和脂肪组织褐变。本研究调查了高脂饮食（HFD）对C57BL/6和TLR2缺陷小鼠内脏脂肪组织（VAT）中低分子量硫化合物的影响。研究重点关注参与HS代谢的关键酶：胱硫醚β-合酶（CBS）、胱硫醚γ-裂解酶（CGL）、3-巯基丙酮酸硫转移酶（MPST）和硫代硫酸盐硫转移酶（TST）。在高脂饮食的C57BL/6小鼠中，MPST活性降低，而CBS水平升高，可能是为了补偿HS的产生。相比之下，高脂饮食的TLR2缺陷小鼠表现出较高的MPST活性，但CBS和CGL活性水平降低，这表明TLR2缺陷减轻了高脂饮食诱导的硫代谢变化。TLR2缺陷小鼠的TST活性较低，表明TLR2在TST活性中具有独立的调节作用。在野生型小鼠中观察到谷胱甘肽水平升高反映的氧化应激增加。有趣的是，仅在C57BL/6正常饮食组的VAT中可检测到半胱氨酸和胱氨酸，而在所有其他组中均不存在。TLR2-/-B6高脂饮食组组织中硫化氢产生能力明显低于C57BL/6高脂饮食组。总之，TLR2调节肥胖中的硫代谢、氧化应激和炎症。TLR2缺陷会破坏HS的产生和氧化还原平衡，可能导致代谢功能障碍，突出了TLR2作为肥胖相关代谢紊乱潜在治疗靶点的地位。
